Cutaneous Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors and Their Management.

Immune checkpoint inhibitors (CPIs) are highly effective in the treatment of various cancers. Immunotherapy enhances antitumor activity by relieving inhibition of T cells responsible for immune surveillance. However, overactivation of T cells leads to immune-related adverse events (irAE), of which cutaneous adverse events are the most common. Examples include pruritus and maculopapular eruption most commonly, psoriasis and bullous dermatoses less commonly, and, rarely, severe, life-threatening eruptions such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. Many of these are autoimmune in nature, and these may present de novo or as recurrence of pre-existing disease. In order to maximize the therapeutic potential of CPIs, it is essential to recognize and effectively manage cutaneous irAE, which can otherwise lead to treatment interruption or discontinuation. This review summarizes the presentation and management of dermatologic adverse events secondary to immune dysregulation as a result of immune checkpoint inhibitor therapy, including the most common (maculopapular eruption, pruritus, lichenoid dermatitis, and vitiligo), less common (psoriasis, bullous pemphigoid, erythema multiforme, eczematous dermatitis, alopecia areata, and granulo-matous and neutrophilic dermatoses), and severe (acute generalized exanthematous pustulosis [AGEP], drug reaction with eosinophilia and systemic symptoms [DRESS], and Stevens-Johnson syndrome or toxic epidermal necrolysis [SJS/TEN]), as well as exacerbation of pre-existing cutaneous autoimmune disease (subacute cutaneous lupus erythematosus, dermatomyositis, eosinophilic fasciitis, leukocytoclastic vasculitis, and scleroderma-like reaction).

Allospecific Memory B Cell Responses Are Dependent on Autophagy.

Long-lived, donor-reactive memory B cells (Bmems) can produce alloantibodies that mediate transplant injury. Autophagy, an intrinsic mechanism of cell organelle/component recycling, is required for Bmem survival in infectious and model antigen systems, but whether autophagy affects alloreactive Bmem is unknown. We studied mice with an inducible yellow fluorescent protein (YFP) reporter expressed under the activation-induced cytidine deaminase (AID) promoter active in B cells undergoing germinal center reactions. Up to 12 months after allogeneic sensitization, splenic YFP+ B cells were predominantly IgD- IgM- IgG+ and expressed CD73, CD80, and PD-L2, consistent with Bmems. Labeled cells contained significantly more cells with autophagosomes and more autophagosomes per cell than unlabeled, naïve B cells. To test for a functional link, we quantified alloantibody formation in mice with B cells conditionally deficient in the requisite autophagy gene ATG7. These experiments revealed absent B cell ATG7 (1) prevented B cell autophagy, (2) inhibited secondary alloantibody responses without altering primary alloantibody formation, and (3) diminished frequencies of alloreactive Bmems. Pharmacological autophagy inhibition with 3-methyladenine had similar effects on wild-type mice. Together with new documentation of increased autophagosomes within human Bmems, our data indicate that targeting autophagy has potential for eliminating donor-reactive Bmems in transplant recipients.

An evaluation of computer-based instruction in microbiology.

There has been a tremendous increase in the availability of computer-based instructional (CBI) materials. Some studies have shown an improvement in learning when CBI is used. However, many researchers believe the current studies are inadequate. While CBI software should be thoroughly tested by developers, as educators, we should be concerned about whether or not the CBI materials we use are improving learning in our classrooms with our students. We present an evaluation of a computer-based hypermedia tutorial that was delivered over our General Microbiology website. We found that CBI was at least as effective as text-based material. However, of all students who used CBI, only those who explored most of the site benefited from using the site. Tracking each student's use of the CBI was critical for understanding who was learning and why.

Carbon-13/carbon-12 isotope fractionation of organic matter associated with uranium ores induced by alpha irradiation.

Analyses of stable carbon isotopes from two sample suites from sandstone uranium (tabular) ores show interesting variations. Organic carbon associated with high-grade uranium ore is heavy (delta(13)C = -16.9 to -19.6 per mil, where delta(13)C = (13)C/(12)C relative to the Pee Dee belemnite standard) relative to the adjacent lower-grade samples (-22.7 to -26.4 per mil). It is suggested that the heavy isotopic values for the are samples are related to a radiation and chemical isotope effect that has occurred mainly because of an alpha-radiation dose of 10(11) rads.